Side effects, e.g., cardiovascular (CV)-related side effects, of pharmaceutical agents can cause significant and often unpredictable clinical problems. For example, prolongation of the QT interval is an undesired and often unanticipated side effect of many cardiac and non-cardiac drugs, as it predisposes the patient to the potentially fatal arrhythmia Torsades de Pointes (TdP). Several pharmaceutical agents have been withdrawn from the U.S. market due to TdP. Many medications only cause QT prolongation when administered in combination with other drugs. QT prolongation can occurs as a result of inherited mutations in ion channel genes, or more commonly as a consequence of drugs that affect cardiac repolarization [1, 2].
Model systems for either IKr blockade or QT prolongation include in vitro assays using cells which have been engineered to express KCNH2 and patch-clamping to directly measure the IKr current in the presence and absence of the drug in question. Voltage sensitive dyes have also been employed in such cells to detect changes in the time course of depolarization and repolarization. Whole animal systems such as guinea pigs, rabbits, or dogs are also used to evaluate drug induced cardiotoxicity.